This Program Grant is intellectually centered around questions concerning the genesis of neuronal architecture. The experiments contained in the individual proposals are highly integrated with one another. Interactions between the growth cone and the environment that regulates neurite growth will be examined by several investigators. Several investigators will address the role of exogenous signals, while others will study the genetic specification of features and ion channels important to growth cone behavior. The ensemble of these various approaches will significantly advance our understanding of the mechanisms underlying the generation of the complex architecture of the nervous system. Bamburg will study the regulation of cytoskeletal elements during neuronal outgrowth, and examine how changes in the organization of these cyotskeletal elements are involved with the motile activity of the growth cone. Mykle's studies will define the role of calpains, which are important calcium dependent proteases that hydrolyze cytoskeletal proteins within the neuronal grow the cone. Kater's work will employ growth cones as assays for important features of the molecular terrain in developing systems. Here, the hypothesis has been made that surface-associated molecules convey information to the neuronal growth cone which is mediated by changes in intracellular calcium. Ishii's work deals with the interactions between nerve and muscle in the context of growth factors, which, as a general class, are known to be of great significance for the behavior of developing neurons. Beam, exploiting the powerful systems he has developed in muscle cells, will directly address questions of calcium channel localization, specification of calcium channel type, and calcium homeostasis with high precision. The material assets and intellectual cohesiveness provided by this Program Project will allow these investigators to use a broad spectrum of approaches to address a central problem of tremendous biological significance in an efficient, integrated and comprehensive fashion.